Gene expression is thought to be the molecular basis of long term synaptic plasticity. Identified sensory neurons mediate well-characterized defensive reflexes in Aplysia. Plasticity of sensory-to-motor synapses underlies both sensitization and habituation of these reflexes. Much work has elucidated the cell- and molecular mechanisms underlying long term sensitization. A facilitatory neurotransmitter, eg serotonin, activates the cAMP-dependent protein kinase, which then is imported into the sensory neuron's nucleus to initiate a cascade of gene expression by phosphorylating the constitutive transcription activator, CREB1. The proteins synthesized are the structural basis for the enhanced transmitter release (facilitation) that underlies the alteration of behavior. We now plan to examine the molecular basis of long term depression (LTD), the physiological process underlying habituation. We showed that short term depression, which lasts for minutes, is produced by brief application of the inhibitory neuropeptide transmitter, FMRFamide; prolonged application results in LTD lasting days or weeks. The decrease in excitatory post-synaptic potentials that characterize synaptic depression is produced by an incompletely analyzed second-message pathway that involves receptor-mediated release of arachidonic acid, which is then converted to active metabolites by 12-lipoxygenase. We now find that the stress MAP kinase, p38, is activated by FMRFa during LTD, as has been reported for depression in pyramidal cells in the vertebrate hippocampus. Once activated, the kinase is imported into the sensory neuron's nucleus. We propose to characterize the signal transduction mechanisms by which p38 kinase operates, both in nucleus and cytoplasm. Since activation of transcription factors is known to induce the synthesis of the proteins needed for the maintenance and consolidation of synaptic plasticity, it is likely that p38 phosphorylates transcription factors. We therefore would identify those factors in order to determine what role p38 kinase plays in producing LTD. Finally we will identify the induced proteins that are required for LTD by differential screening. The mechanisms underlying synaptic plasticity are important because they are likely to be disturbed in mental disorders (schizophrenia and depression), and to play a crucial role in drug addiction. Aplysia neurons offer a convenient experimental system for approaching these processes successfully.